Adhesive compositions for hard tissues

ABSTRACT

An adhesive composition is provided which is suitable for the bonding of polymeric materials, in whole or in part, such as composite resins, or methacrylate-containing glass-ionomer filling materials, to tooth enamel, or tooth dentin, or to other hand tissues of the human body, such as bone. The composition comprises an unsaturated carboxylic acid ester, an unsaturated phosphate ester and other crosslinking agents. The especially preferred phosphates (which are provided as new compounds) are those of formula (I) in which: R 1  is a hydrogen atom, alkyl C 1 -C 4 , or CN; R is an aliphatic, cycloaliphatic or aryl radical containing from 1 to 10 carbon atoms and having a valence of n+1; n is an integer from 1 to 5, preferably from 3 to 5.

RELATED APPLICATIONS

This application is a continuation in part of and claims the benefit ofPCT Application PCT/US99/18582 filed Aug. 17, 1999, which designated theUnited States and claims the priority benefit of U.S. ProvisionalApplication No. 60/096,838 filed Aug. 18, 1998, the disclosures of whichare incorporated by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to adhesive compositions, especially those whichare suitable for promoting the bonding of dental restorative materials,especially those that have polymeric components, to tooth enamel, or totooth dentin or other hard tissues of human body, such as bone. Therestorative materials can be polymers, or resins, or can containpolymers or resins in whole, or in part, and comprise materials such asdental composite resins, or methacrylate containing glass ionomerfilling materials, or glass ionomer filling materials havingethylenically unsaturated bonds, or they can comprise resin cements.

2. Background of the Invention

The bonding of restorative materials to tooth structure has been animportant goal of the dental profession. Such bonding has the benefitsof (1) efficiently retaining materials to tooth structure without theneed for mechanically locking filling materials into teeth, the latterbeing a procedure which requires the removal of otherwise healthy toothstructure, and which has been the historical way that materials havebeen retained, (2) simplifying treatment procedures by eliminating theneed for forming precise geometric shapes of teeth when surgicalinterventions are made, (3) enhancing the quality of interfaces betweenfilling materials by improving the seal between tooth structure andfilling materials.

Filling materials in dentistry are generally used to restore teeth toform and function, as well as seal the tooth against oral fluids andbacteria. Directly filling materials are those that are placed in atooth, and then hardened in the tooth. The most commonly used directfilling polymeric materials are polymer-matrix composite resins, andresin-containing or resin modified glass ionomer filling materials.Compositions for bonding these polymeric materials to tooth structureare especially useful.

Composite resins general comprise a resin matrix, an inorganic fillerphase and some coupling agents. The resin matrix generally comprises amonomer system, an initiator system and other stabilizers. The monomersystem comprises unsaturated compounds. These compounds generallycomprise one or more esters of ethylenically unsaturated carboxylicacids and the adduct of bisphenol A and glycidyl methacrylate (Bis-GMA),such as triethyleneglycol dimethacrylate (TEGDMA), ethyleneglycoldimethacrylate (EGDMA) and2,2-bis-[4-(2-hydroxy-3-methacrylyloxypropoxy)phenyl]-propane ether(Bis-GMA) in U.S. Pat. No. 3,066,112 to Bowen. Another class ofunsaturated materials are urethane dimethacrylates, such as the1,6-bis(methacrylyloxy-2-ethoxycarbonylamino-2,4,4-trimethylhexane(UEDMA) which is synthesized from 2-hydroxyethyl methacrylate and2,4,4-trimethylhxamethylenedisocynanate.

When composite resins are placed in a tooth cavity and cured, thehardening (“polymerization”) of the material usually results inshrinkage. This shrinkage leads to marginal gap formation, allowing forthe passage of fluid, bacteria, molecules or ions between therestoration and the cavity wall, which may result in secondary caries,marginal discoloration and pulpal damage. The longevity of therestoration will be reduced by this micro-shrinkage. A strong andpermanent bond between the wall of the cavity and the restorative willlead to good sealing, and is beneficial.

Bonding to dental surfaces is usually achieved by the use of acidconditioners, primers and adhesive resins. Primers, which can be appliedsequentially, or simultaneously with adhesive resins, generally containone or more polar groups and unsaturated groups. It is assumed that thepolar groups will bond either to the inorganic crystal lattice (apatite)portion of tooth structure, or to the polar part of collagen in thetooth, this occurring by chemical or hydrogen bonding, and/or bymicromechanical retention due to the formation of a hybrid layer. Thehybrid layer, which has been well characterized, is formed by theinfiltration of the primer into a demineralized dentin zone, thedemineralization having resulted from acid etching of the tooth. Theunsaturated groups of the primer will bond with resin overlayers by freeradical polymerization. The polar groups are normally a phosphate, anamino acid or amino alcohol, or a dicarboxylic acid.

U.S. Pat. No. 4,368,043 to Yamauchi, incorporated herein by reference,discloses an adhesive cementing agent for the human body. This agentcontains a phosphoric or phosphonic acid ester compound, or a highmolecular weight compound obtained by polymerizing the compound whetheralone or as co-monomer units.

U.S. Pat. No. 4,514,342 to Billington, incorporated herein by reference,describes an adhesion promoter, suitable for improving the adhesion ofcomposite dental material to tooth enamel. This adhesion promotercontains volatile organic solvent and a polyethylenically unsaturatedmonophosphate or salt, which contains a monophosphate radical and atleast three ethylenically unsaturated groups.

A biologically compatible adhesive is disclosed in U.S. Pat. No.4,657,941 to Blackwell, incorporated herein by reference. This adhesiveis shelf stable as a single component adhesive and includes a mixture ofan adhesive promoting and polymerizable monomer system. A free radicalpolymerizable monomer or prepolymer having ethylenic unsaturation and aphosphorus-containing adhesion promoter, having a free radicalpolymerization catalyst and an accelerator for the catalyst are includedin this system.

While the adhesion between filling materials and enamel or dentin of thetooth is improved by usage of an adhesive promoter, some disadvantages,such as not having great bonding strength, or too great a viscosity forhandling of some component exists in some adhesives.

SUMMARY OF THE INVENTION

An object of this invention is to provide an adhesive composition, whichis suitable for promoting the adhesion of restorative materials to toothenamel, tooth dentin or other hard tissues of human body.

It is a further object of this invention to provide an adhesivecomposition which is suitable to be used with other hard tissues of thebody.

It is a further object of this invention to provide an adhesivecomposition, which, when used with other resins, can seal dentinaltubules.

This composition contains a volatile organic solvent and anethylenically unsaturated monomer and phosphate, which contains a mono-,or di-phosphate radical and at least three ethylenically unsaturatedgroups.

The preferred solvent is a lower aliphatic alcohol and carbonylcompound. The solution is preferably from 1 to 50% by weight of thetotal solution of ethylenically unsaturated monomer and phosphate.

The ethylenically unsaturated monomer in the composition is a mono-, di,tri, or multifunctional acrylic monomer, such as 2-hydroxyethylmethacrylate, 1,3-butanediol dimethacrylate, 1,4-butanedioldimethacrylate, or 1,4-butanediol divinyl ether.

The ethylenically unsaturated phosphate is the reaction product ofalcohol containing unsaturated allyl ether and phosphorus oxychloride orother phosphorus containing compounds.

A very important aspect of this invention are the novel compounds arerepresented by following formula:

in which:

R₁, is a hydrogen atom, alkyl C₁-C₆, (preferably C₁-C₄ when alkyl), orCN,

R is an aliphatic, cycloaliphatic or aryl radical containing from 1 to10 carbon atoms and having a valence of n+1,

n is an integer from 1 to 5, preferably from 3 to 5, which can be usedas a primer for hard tissues.

DETAILED DESCRIPTION OF THE INVENTION

It has been found, in accordance with the present invention, that theadhesion of filling materials to enamel; or to dentin, may beconsiderably improved by first applying the composition of thisinvention to prepared dentin or enamel. The preparation procedure caninvolve the application of an acid to the tooth surface (where bondingis required), a technique which is known as acid-etching, and which iswell known in the dental art. On enamel, the treatment of tooth surfaceswith acid preferentially removes inter-rod material, and createsmicropores into which the invention, in combination with other resins,can penetrate to form mechanical anchors (tags), when hardened. Ondentin, the acid dissolves the mineral phase of dentin, and exposes afibrillar network of collagen. It is believed that the adhesion resultsfrom the penetration of the said composition into the exposed collagennetwork, and subsequent hardening of the said composition in conjunctionwith other resins placed as overlayers. These overlayers (known asintermediary resins, or adhesive resins) bond with restorative materialsor cements which are subsequently placed on the overlayers.

The adhesive composition, in accordance with this invention, consists ofa volatile organic solvent and an ethylenically unsaturated monomer andphosphate, which contains a mono-, or di-phosphate radical and at leastthree ethylenically unsaturated groups.

The preferred solvent is a lower aliphatic alcohol and carbonylcompounds. The most preferred solvent is acetone. The concentration ofthe solvent in solution is from 1 to 90% by weight of the total solutionof ethylenically unsaturated monomer and phosphate, preferably from 10to 80% of the total solution of ethylenically unsaturated monomer andphosphate, and most preferably from 30 to 70% by weight.

The ethylenically unsaturated monomer in the composition is a mono-, di,tri, or multifunctional acrylic monomer, such as 2-hydroxyethylmethacrylate, 1,3-butanediol dimethacrylate, 1,4-butanedioldimethacrylate, or pentaerythritol triacrylate. The most preferredmonomer is 2-hydroxyethyl methacrylate. The concentration of monomer inthe composition is from 1 to 60% by weight. The preferred concentrationis from 20 to 50% by weight, and the most preferred concentration isfrom 30 to 40% by weight.

The ethylenically unsaturated phosphate is a reaction product of alcoholcontaining unsaturated allyl ether and phosphorus oxychlonde or otherphosphorus containing compounds.

The unsaturated allyl ether in the phosphate are preferably vinylgroups.

The introduction of phosphate in the composition is very important. Itis presumed that the phosphate will interact with inorganic componentsof a tooth, or other hard tissues, either by forming a complex with thecalcium ion or forming a chemical or hydrogen bond with the phosphate,with mineral in enamel, or with mineral that is left in dentin afteretching. The phosphate may also be important for interacting withcollagen. A very important aspect of this invention is that the newcompounds have the following formula:

in which:

R₁, is a hydrogen atom, alkyl C₁-C₄ or alkyl C₁-C₆, or CN,

R is an aliphatic, cycloaliphatic or aryl radical containing from 1 to10 carbon atoms and having a valence of n+1,

n is an integer from 1 to 5, preferably from 3 to 5.

The preferred concentration of phosphate in the composition is from 2 to70% by weight, although in principle useful results are obtainable in arange of 2-17% by weight. In another aspect, a range of 5 to 40% byweight can be used. The most preferred is from 5 to 10% by weight.

A solution containing the phosphate compound and which is applied to atooth surface can be hardened simultaneously with resin overlayers whichalready contain hardening agents. The solution of PTEPAE can also behardened by the addition of known hardening agents, such ascamphorquinone, or benzoyl peroxide.

The invention will be understood by the following examples, which aregiven by way of illustration only:

EXAMPLE 1 Pentaerythritol Triallyl Ether Monophosphate Acid Ester(PTEPAE)

A solution containing phosphorus oxychloride (15.3 g) in dry ether (60ml), or methyl ter-butyl ether, isopropyl acetate, di-isopropyl ether,but preferably dry ether, was slowly dropped into a solution containingtechnical pentaerythritol triallyl ether (9.9 g) and triethylamine (3.8g) in dry ether (60 ml) at 0° C. The solution is stirred for 16 hours atroom temperature. The precipitation of the triethylamine hydrochlorideis filtered off, and the solution is hydrolyzed by the addition of theether solution into ice water (100 ml) with stirring. The mixture isseparated, and the ether layer is basified with sodium carbonatesolution to obtain a pH=10, and then acidified with hydrochloric acid toobtain pH=4. The ether layer is extracted and dried by magnesiumsulphate. The ether is extracted under reduced pressure to give thetitle compounds as a clear colorless liquid. The H¹ NMR spectrum of thiscompound shows peaks around 6.2-5.8, 5.6-5.1, 4.5-4.1, 4.0-3.8, 3.6-3.4,2.2-2.0, 1.5-1.2, 1.0-0.8 ppm.

EXAMPLE 2

Five solutions each containing acetone and one of the following primers:pentaerythritol triallyl ether (PTE) (10% by weight), PTEPAE (10% byweight), 2-hydroxylerhyl methacrylate (HEMA) (35% by weight), a mixtureof HEMA (35% by weight) and PTEPAE (10% by weight), or a mixture of HEMA(35% by weight) and PTE (10% by weight), were prepared. In thesesolutions, the primer was provided according to the prior listedpercentages, with the balance being acetone. Maleic acid was dissolvedinto water to obtain a pH=0.8, although other acids such as phosphoricacid, citric acid, or nitric acid, having a pH ranging from of 0.5 to4.0, most preferably from 0.8 to 3.0, can be used. Bond strength foreach of the solutions was determined. For the bond strength test, theocclusal enamel of extracted caries-free human teeth was removed with arotating diamond blade using a copious amount of water to expose thedentin surface. The sectioned teeth were mounted in PVC rings usingpolymethylmethacrylate with the dentin surface being 0.5 nm above theedge of the ring. The mounted teeth were ground with a Buehler MetaservGrinder (Buehler LTD, U.K.) using 1200-grit paper at 150 rpm and 5 psiuntil a uniformly reflective, smooth, and flat dentin surface appeared.Multiple layers of the priming solution were placed on the dentinsurface. Note that, as part of the method, it is important to placemultiple layers of the adhesive on the surface so that after saidetching, full saturation of the demineralized layer by the primingsolutions occur. After the primers were placed, a commercialintermediary resin, D/E resin (BISCO, Itasca, Ill., USA. Reorder No.B-2502A) and AELITEFIL composite (BISCO, Itasca, Ill., USA. Lot No.089226) were sequentially placed on the surface of dentin according tothe procedure described in the reference Stangel et al., Journal ofAdhesion, Vol. 47, p.p. 133-149,1994, incorporated herein by referencein its entirety. After 24 hours storage in water, all samples wereloaded on Instron Series IX Automated Materials Testing System, andtested to failure at a cross-head speed oft nzm/minute. The results areshown in TABLE 1.

TABLE 1 Bond Strength of composite resin to dentin Primer Acid TreatmentAverage Peak Composition of Dentin Stress (MPa) Number of samples PTE noetch 5.0 10 PTEPAE no etch 6.5  8 PTEPAE Etched 1.8  7 HEMA Etched 12.1  5 HEMA + PTEPAE Etched 19.9  12 HEMA + PTE Etched 9.0  6

EXAMPLE 3

A mixture of 2-hydroxylethyl methacrylate (HEMA) (35% by weight) andPTEPAE (10% by weight), the balance being acetone, was prepared. Samplesfor testing the bond strength of the solution to dentin were prepared asdescribed in example 2. The samples were immersed in a water bath at 37°C. for 24 hours, and tested to failure as described in Example 2. Themean peak stress at failure, for seven samples was 20.5 MPa.

EXAMPLE 4

A mixture of 2-hydroxylethyl methacrylate (HEMA) (35% by weight) andPTEPAE (10% by weight), the rest being acetone was prepared. Samples fortesting the bond strength of the solution to dentin were prepared asdescribed in example 2, except the dentin was etched by phosphoric acidhaving a concentration of about 35% (by weight). The samples wereimmersed in a water bath at 37° C. for 24 hours, and tested to failureas described in Example 2. The mean peak stress at failure, for sixsamples was 25.5 MPa.

EXAMPLE 5

A mixture of 2-hydroxylethyl methacrylate (HEMA) (35% by weight) andPTEPAE (10% by weight), the rest being acetone was prepared. Samples fortesting the bond strength of the solution to dentin were prepared asdescribed in Example 2. The samples were immersed in a water bath at100° C. for two hours, and tested to failure as described in Example 2.The mean peak stress at failure, for eight samples was 17.3 MPa.

EXAMPLE 6

A flat surface of bovine enamel was placed in a bedding ofpolymethylmethacrylate as described for dentin samples in Example 2. Thesurface of the enamel was etched with phosphoric acid having aconcentration of about 35% (by weight). The surface was then treatedwith a solution consisting of a mixture of 2-hydroxylethyl methacrylate(HEMA) (35% by weight) and PTEPAE (10% by weight), the rest beingacetone. After allowing the acetone to evaporate, a solution consistingof a 1:1 mixture of bisphendl-A glycidyl methacrylate (Bis-GMA) andtriethyleneglycol dimethacrylate (TEGDMA) was applied. Composite resinwas positioned on the surface, and the materials were hardened byexposure to a visible light. After 24 hours storage in water, thesamples were tested to failure as described in Example 2. The mean peakstress at failure, for seven samples was 18.0 MPa.

What is claimed is:
 1. An ethylenically unsaturated monophosphaterepresented by the formula:

in which: R₁, is a hydrogen atom, alkyl C₁-C₄, or CN, R is an aliphatic,cycloaliphatic or aryl radical containing from 1 to 10 carbon atoms andhaving a valence of n+1, and n is an integer from 1 to
 5. 2. Thecompound of claim 1, wherein the ethylenically unsaturated monophosphateis pentaerythritol triallyl ether monophosphate acid ether.
 3. Thecompound of claim 1, wherein the ethylenically unsaturated monophosphateis pentaerythritol trimethyl ether monophosphate acid ether.
 4. Thecompound of claim 1, wherein n is an integer from 3 to
 5. 5. Acomposition comprising at least one monophosphate according to claim 1and a 2-hydroxylethyl methacrylate.
 6. The compound of claim 1, whereinR represents a cycloaliphatic radical.
 7. The compound of claim 1,wherein R represents an aryl radical.
 8. The compound of claim 1,wherein n is greater than
 1. 9. The compound of claim 6, wherein n isgreater than
 1. 10. The compound of claim 7, wherein n is greater than1.